Details

Autor(en) / Beteiligte

• Tiseo, Marcello
• Giovannetti, Elisa
• Tibaldi, Carmelo
• Camerini, Andrea
• Di Costanzo, Francesco
• Barbieri, Fausto
• Burgers, Jacobus A
• Vincent, Andrew
• Peters, Godefridus J
• Smit, Egbert F
• Ardizzoni, Andrea

Titel

Pharmacogenetic study of patients with advanced non-small cell lung cancer (NSCLC) treated with second-line pemetrexed or pemetrexed–carboplatin

Ist Teil von

• Lung cancer (Amsterdam, Netherlands), 2012-10, Vol.78 (1), p.92-99

Ort / Verlag

Oxford: Elsevier Ireland Ltd

Erscheinungsjahr

2012

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• Abstract Purpose To correlate candidate polymorphisms affecting pemetrexed and carboplatin activity with clinical outcome of patients with advanced non-small cell lung cancer (NSCLC) treated in second-line with pemetrexed or pemetrexed plus carboplatin. Methods Functional polymorphisms in thymidylate synthase (TS), reduced folate carrier (RFC), gamma-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR) and xeroderma pigmentosum group D (XPD) genes were evaluated in 208 patients either treated within randomized phase II trials NVALT-7 and GOIRC-02.2006, comparing second-line pemetrexed with pemetrexed plus carboplatin, or with the same regimens outside of these trials. Univariate and multivariate analyses correlated genotyping data with response, clinical benefit, toxicity, progression-free (PFS) and overall survival (OS) using Pearson- χ2 test, log-rank test and Cox proportional hazards model. Results Patients harboring the MTHFR-T667T variant had significantly longer PFS (5.4 versus 3.4 months; p = 0.012) and OS (16.4 versus 8.5 months; p = 0.026) than patients with CC–CT genotypes. No correlation was observed for other polymorphisms, except for XPD-Gln751Gln , which was associated with shorter PFS ( p = 0.021) and OS ( p = 0.044) in the subgroup of patients treated with pemetrexed plus carboplatin. Multivariate analysis confirmed the independent prognostic significance of MTHFR-C677T both in risk of disease progression ( CC–CT genotypes hazard ratio [HR] 1.94, 95%CI 1.15–3.28; p = 0.012) and of death (HR 2.00, 95%CI 1.12–3.54; p = 0.018). Conclusions MTHFR-C667T polymorphisms appear to predict survival differences in pemetrexed-treated NSCLC. These results should be validated in larger and adequately designed prospective studies using pemetrexed.